The present invention relates to novel amino acid phenyl ethers for the treatment of immunological diseases, inflammation, obesity, hyperlipidemia, hypertension, neurological diseases and diabetes.
The principal elements of the immune system are macrophages or antigen-presenting cells, T cells and B cells. The role of other immune cells such as NK cells, basophils, mast cells and dendritic cells are known, but their role in primary immunologic disorders is uncertain. Macrophages are important mediators of both inflammation and providing the necessary xe2x80x9chelpxe2x80x9d for T cell stimulation and proliferation. Most importantly macrophages make IL 1, IL 12 and TNF-xcex1 all of which are potent pro-inflammatory molecules and also provide help for T cells. In addition, activation of macrophages results in the induction of enzymes, such as cyclooxygenase II (COX-2), inducible nitric oxide synthase (iNOS) and production of free radicals capable of damaging normal cells. Many factors activate macrophages, including bacterial products, superantigens and interferon gamma (IFN xcex3). It is believed that phosphotyrosine kinases (PTKs) and other undefined cellular kinases are involved in the activation process.
Cytokines are molecules secreted by immune cells that are important in mediating immune responses. Cytokine production may lead to the secretion of other cytokines, altered cellular function, cell division or differentiation. Inflammation is the normal response to injury or infection. However, in inflammatory diseases such as rheumatoid arthritis, pathologic inflammatory processes can lead to morbidity and mortality. The cytokine tumor necrosis factor-alpha (TNF-xcex1) plays a central role in the inflammatory response and has been targeted as a point of intervention in inflammatory disease. TNF-xcex1 is a polypeptide hormone released by activated macrophages and other cells. At low concentrations, TNF-xcex1 participates in the protective inflammatory response by activating leukocytes and promoting their migration to extravascular sites of inflammation (Moser et al., J Clin Invest, 83:444-55, 1989). At higher concentrations, TNF-xcex1 can act as a potent pyrogen and induce the production of other pro-inflammatory cytokines (Haworth et al., Eur J Immunol, 21:2575-79, 1991; Brennan et al., Lancet, 2:244-7, 1989). TNF-xcex1 also stimulates the synthesis of acute-phase proteins. In rheumatoid arthritis, a chronic and progressive inflammatory disease affecting about 1% of the adult U.S. population, TNF-xcex1 mediates the cytokine cascade that leads to joint damage and destruction (Arend et al., Arthritis Rheum, 38:151-60, 1995). Inhibitors of TNF-xcex1, including soluble TNF receptors (etanercept) (Goldenberg, Clin Ther, 21:75-87, 1999) and anti-TNF-xcex1 antibody (infliximab) (Luong et al., Ann Pharmacother, 34:743-60, 2000), have recently been approved by the U.S. Food and Drug Administration (FDA) as agents for the treatment of rheumatoid arthritis.
Elevated levels of TNF-xcex1 have also been implicated in many other disorders and disease conditions, including cachexia, septic shock syndrome, osteoarthritis, inflammatory bowel disease such as Crohn""s disease and ulcerative colitis etc.
Excessive production of IL-6 is implicated in several disease states, it is highly desirable to develop compounds that inhibit IL-6 secretion.
The cytokine IL-1xcex2 also participates in the inflammatory response. It stimulates thymocyte proliferation, fibroblast growth factor activity, and the release of prostaglandin from synovial cells.
Elevated or unregulated levels of the cytokine IL-1xcex2 have been associated with a number of inflammatory diseases and other disease states, including but not limited to adult respiratory distress syndrome, allergy, Alzheimer""s disease etc.
Since overproduction of IL-1xcex2 is associated with numerous disease conditions, it is desirable to develop compounds that inhibit the production or activity of IL-1xcex2.
It will be appreciated from the foregoing that, while there have been extensive prior efforts to provide compounds for inhibiting, for example, TNF-xcex1, IL-1, IL-6, COX-2 or other agents considered responsible for immune response, inflammation or inflammatory diseases, e.g. arthritis, there still remains a need for new and improved compounds for effectively treating or inhibiting such diseases.
There appears to be a correlation of TNF-xcex1 to adipogenesis (obesity) and other metabolic disorders such as diabetes mellitus. Although, in the past two decades there has been an explosive increase in number of people diagnosed with diabetes worldwide [Amos A., McCarty, D., Zimmet, P. (1997) Diabetic Med. 14, S1-S85; King, H., Aubert, R., Herman, W. (1998) Diabetes Care, 21, 1414-1431], there has been relatively little development of new therapeutics for the treatment of diabetes and its associated conditions [Moller, D. E. (2001) Nature 414, 821-827]. Diabetes exists in two types: insulin dependent Type-I and non-Insulin dependent (insulin-resistant) Type-I. Type-II insulin-resistant diabetes mellitus accounts for 90-95% of all diabetes. This syndromic metabolic disorder currently affects more than 150 million people worldwide and is projected to grow to 300 million by year 2005 [Amos, A., McCarty, D., Zimmet, P. (1997) Diabetic Med. 14, S1-S85; Kopelman, P. G. Hitaman, G. A. (1998) Lancet, 352, SIV5). The main force driving this increase in incidence of type II diabetes is an increase in obesity, the single most important contribution to the pathogenesis of type II diabetes [Kopelman, P. G., Hitaman, G. A. (1998) Lancet, 352, SIV5].
At present, therapy for type II diabetes relies mainly on several approaches intended to reduce the hyperglycemia itself. These are: sulfonylureas and related insulin secretogens that are known to release more insulin from pancreatic xcex2 cells; metformin, that acts to reduce hepatic glucose production; peroxisome proliferator-activated receptor (PPAR) agonists that enhances insulin action; a-glucosidase inhibitors that slow down absorption of glucose from the gut; and insulin itself, that suppresses glucose production and augments glucose utilization (summarized in table I below). All of these therapies have limited efficacy, limited tolerability and significant mechanism-based side effects. Of particular concern is the tendency for most treatment to enhance body weight gain. Several current treatments for type II diabetes are associated with episodes of hypoglycemia, and few of the available therapies adequately address underlying defects such as obesity and a phenomenon known as insulin resistance. Among these oral medications, sulfonylureas represent the oldest and widely used form of treatment. Many patients who respond to sulfonylureas initially become refractory to the treatment over time (secondary failure). Besides glucose level and obesity, type II diabetes is now linked with high level of triglycerides and cholesterol. Therefore, there is a need for new classes of drugs addressing the underlying issue of metabolic defects (increasingly known as Syndrome-X) such as obesity, hyperglycemia and hyperlipidemic conditions to address type II diabetes and its associated condition.
The present invention, relates to novel amino acid phenyl ethers of formula (I) 
their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, wherein - - - represents optional double bond; Y represents oxygen, sulfur or NR, wherein R represents hydrogen or alkyl; Z represents oxygen or sulfur; R1, R2, R3 and R4 may be same or different and independently represent hydrogen, halogen, hydroxy, nitro, cyano, formyl, amino, alkyl, alkoxy group; A represents a bond or substituted or unsubstituted aryl, heterocyclyl or heteroaryl ring; X represents an alpha amino carboxylic acid or its derivatives bonded to A or Y through its alpha side chain.
The present invention also relates to a process for the preparation of the above said novel compounds, their analogs, their derivatives, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, novel intermediates and pharmaceutical compositions containing them. Tautomeric forms are isomeric forms which exists in a state of equilibrium capable of reacting according to either form. Stereoisomers include configurational isomers, such as cis- and trans-double bonds, as well as optically active isomers having different spatial arrangements of their atoms. Polymorphs are molecules which can crystallize in two or more forms. Solvates are molecular or ionic complexes of molecules or ions of solvent with those of a solute. An alpha-amino carboxylic acid includes, but is not limited to, naturally-occurring amino acids. The alpha side chain is a group, including hydrogen, covalently bonded to the alpha carbon of an alpha-amino carboxylic acid. Analogs include those compounds which differ by substitution of an oxygen, sulfur, nitrogen or carbon atom in place of such an atom. Analogs also include atoms of the same family of the Periodic Table, such as F, Cl, Br, I, As. Derivatives include compounds resulting from routine functionalizing of atoms, such as, derivatives found by protecting amino or carboxyl groups by carboxylation or esterification, respectively.
The compounds of the present invention are effective in lowering blood glucose, serum insulin, free fatty acids, cholesterol and triglyceride levels and are useful in the treatment and/or prophylaxis of diabetes. The compounds of the present invention are effective in treatment of obesity, inflammation, autoimmune diseases such as such as multiple sclerosis and rheumatoid arthritis. Surprisingly, these compounds increase the leptin level and have no liver toxicity.
Furthermore, the compounds of the present invention are useful for the treatment of disorders associated with insulin resistance, such as polycystic ovary syndrome, as well as hyperlipidemia, coronary artery disease and peripheral vascular disease, and for the treatment of inflammation and immunological diseases, particularly those mediated by cytokines such as TNF-xcex1, IL-1, IL-6, IL-1xcex2 and cyclooxygenase such as COX-2.